EP1701721A1 - Verwendung von pilocarpin für die behandlung von hypotyalismus - Google Patents

Verwendung von pilocarpin für die behandlung von hypotyalismus

Info

Publication number
EP1701721A1
EP1701721A1 EP05717659A EP05717659A EP1701721A1 EP 1701721 A1 EP1701721 A1 EP 1701721A1 EP 05717659 A EP05717659 A EP 05717659A EP 05717659 A EP05717659 A EP 05717659A EP 1701721 A1 EP1701721 A1 EP 1701721A1
Authority
EP
European Patent Office
Prior art keywords
treatment
hyposialies
pilocarpine
medicament
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP05717659A
Other languages
English (en)
French (fr)
Other versions
EP1701721B1 (de
Inventor
Philippe Perovitch
Marc Maury
Jean Deymes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DEYMES, JEAN
MAURY, MARC
Perovitch Philippe
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to PL05717659T priority Critical patent/PL1701721T3/pl
Priority to SI200530909T priority patent/SI1701721T1/sl
Publication of EP1701721A1 publication Critical patent/EP1701721A1/de
Application granted granted Critical
Publication of EP1701721B1 publication Critical patent/EP1701721B1/de
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a composition for the treatment of hyposialies comprising pilocarpine.
  • This composition has multiple direct effects in the bucco-pharyngeal sphere.
  • Radiation therapy is one of the major treatments in the case of cancers of the ENT sphere which leads to significant adverse effects.
  • Salivary production is dependent on: - salivary main glands: parotid, submaxillary and sublingual, and - accessory salivary glands that are disseminated throughout the entire surface of the oral mucosa: labial, jugal, palatal and velar, lingual and subcutaneous. lingual.
  • hyposialies can be broken down into: - transient hyposialias: pre-menopausal or menopausal state, medications such as oral contraceptives, diuretics, cardio-vascular products, anti-inflammatory drugs, anti-histamines, antidepressants, psychotropic drugs, tranquillizers, anti-insonials, and permanent hyposialies: evolution of autoimmune diseases, syndrome of Gujarot-Sjogren which affects the exocrine and mucous glands, iatrogenic effects generated by treatment with therapeutic irradiations generating a deficit that can nevertheless be compensated by therapeutic stimulation.
  • medications such as oral contraceptives, diuretics, cardio-vascular products, anti-inflammatory drugs, anti-histamines, antidepressants, psychotropic drugs, tranquillizers, anti-insonials
  • permanent hyposialies evolution of autoimmune diseases, syndrome of Gujarot-Sjogren which affects the exocrine and mucous glands, iatrogenic effects generated by treatment with
  • pilocarpine which is an alkaloid extract pilocarpus leaves of different varieties jaborandi, pennatifolius, microphyllus.
  • Pilocarpine of composition 11.H16N2O2 appears to be an oily, viscous, light-sensitive and amphiphilic liquid which allows dissolution both in water and much more readily in a solvent or composition of organic solvents. .
  • the dose is 5 mg of pilocarpine per tablet to be administered 3 times a day, or 15 mg of pilocarpine per day, or even up to 30 mg per day for some more cases. severe. In fact, it has been found that this taking of large doses over several weeks is the cause of significant adverse side effects such as nausea, sweating, dizziness, hot flashes or asthenia.
  • a first consequence of the oral route is the passage through the digestive tract which leads to variable absorption and bioavailability because the first passage through the liver causes the active ingredient to undergo significant degradation in the form of metabolites no longer having pharmacological activities.
  • An overdose must be provided so that the effect of the remaining part reaches the areas of oral and submaxillary activity.
  • Another consequence is a delayed effect of the active ingredient since the first action of pilocarpine is exercised with a delay of 0.45 to 1 hour after setting.
  • composition including pilocarpine according to the present invention makes it possible to strongly limit the side effects related to an oral absorption, improves the dose / effect ratio and confers a strong improvement of the bioavailability.
  • the composition according to the present invention consists in administering pilocarpine base or in the form of salts, hydrochloride or nitrate, in a specific galenic form of a slow-disintegrating sub-lingual tablet allowing it to: - have direct and instant access to muscarinic receptors of submucosal glandular structures, - to protect and be stable against light, temperature and oxidation, - to dissolve and settle locally by associating intimately with the tissues of the bucco-pharyngeal sphere.
  • pilocarpine is associated with at least one bioadhesive polymer, at least one buffer and at least one lubricant.
  • a softener a hydrophilic substance
  • the tablet formulation may provide dimensions capable of avoiding swallowing and direct passage to the digestive tract.
  • An example of a formulation for a tablet for sub-lingual use is: - pilocarpine base or in the form of salt: 2.5 mg - magnesium stearate: 10.0 mg - sodium or disodium hydrogenphosphate: 90.0 mg - methocel 100 : 50.0 mg - PolyEthyleneGlycol 6000: 40.0 mg - hyaluronic acid: 20.0 mg - lysozyme hydrochloride: 15.0 mg - sorbitol qs tablet 1000 mg: 772.5 mg
  • the pH buffer based on sodium or disodium hydrogenphosphate can be replaced by sodium carbonate or bicarbonate.
  • Magnesium stearate is a lubricant suitable for the manufacture of tablets and the PEG, in addition to its lubricating properties, is hydrophilic giving the composition a softening effect.
  • Mention may also be made as substances having the same functionalities as PE6 family of cellulosic derivatives, gums or other polymers.
  • the family of cellulose derivatives comprises in particular: sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylpropylose, methylcellulose or metolose, or ⁇ -carboxymethylcellulose.
  • guar xanthan
  • acacia Suitable polymers for this application include: - alginic acid and derivatives, - carboxy-vinyl polymer - carbomer - macrogols - gelatin - povidone, or - pectins.
  • Lysozyme hydrochloride can be added advantageously to compensate for physiological salivary lysozyme deficiency in the case of hyposialies.
  • the dosage is to be adapted but a range of proportions is between 5 and 30 mg for a 1000 mg tablet. .
  • a mass substrate which is of low molecular weight and preferably hygroscopic.
  • hygroscopic There may be mentioned the family of polyols, sorbitol, mannitol or xylitol, but also glucose or lactose. This hygroscopic character induces the implementation of fluid movements from the oral cavity to this mass substrate facilitating the dissolution of pilocarpine, distribution and adhesion to mucosal tissues.
  • composition according to the present invention leads to the positive consequences which are now enumerated. Thanks to the composition according to the present invention, pilocarpine causes a first direct effect because it is immobilized in direct contact with the muscarinic receptors present in the various salivary glandular structures, submucosal glands endo-oral and submaxillary.
  • Pilocarpine thus maintained in contact, is sufficiently well dissolved and bioavailable to be absorbed through the phospholipid structures of the cell walls of the stratified epithelium of the mucosa.
  • This first effect obtained is direct, but not only does pilocarpine gain access to the saliva production groups, but it also partly passes into sub and per lingual venous micro vascularization.
  • pilocarpine is distributed in minutes to sub-maxillary glandular packs, which is a second action slightly offset in time and under a different mechanism.
  • This formulation thus makes it possible to avoid the passage through the liver and the associated metabolism. The amount can be reduced and the dose / effect ratio is greatly increased.
  • the effective concentration thresholds of the composition according to the present invention are much lower and often lower than the triggers at the digestive, cardiovascular, urinary, and provoking levels of hypersudations, flushing or nausea.
  • the pilocarpine which remains circulating in the arterial way, necessarily in very small quantity, it always joins the hepatic system by the hepatic artery and is definitely metabolized. This makes it possible to respect the metabolism of detoxification.
  • the treatment with low doses and a perfectly stable formulation also makes it possible to use a very flexible dosage, more precisely adapted to each patient according to the often very variable requirements, with values adjusted to the nearest 0.5 mg.
  • Such a formulation thus allows a permanent intake of pilocarpine because lateral effects are reduced.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP20050717659 2004-01-09 2005-01-07 Verwendung von pilocarpin für die behandlung von hypoptyalismus Not-in-force EP1701721B1 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PL05717659T PL1701721T3 (pl) 2004-01-09 2005-01-07 Zastosowanie pilokarpiny do leczenia zmniejszonego wydzielania śliny
SI200530909T SI1701721T1 (sl) 2004-01-09 2005-01-07 Uporaba pilokarpina za zdravljenje hipoptializma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0450050A FR2864901B1 (fr) 2004-01-09 2004-01-09 Composition pour le traitement au contact des hyposialies, incluant de la pilocarpine et a effets multiples
PCT/FR2005/050012 WO2005067924A1 (fr) 2004-01-09 2005-01-07 UTILISATION DE LA PILOCARPINE POUR LE TRAITEMENT des HYPOSIALIES

Publications (2)

Publication Number Publication Date
EP1701721A1 true EP1701721A1 (de) 2006-09-20
EP1701721B1 EP1701721B1 (de) 2009-12-09

Family

ID=34685043

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20050717659 Not-in-force EP1701721B1 (de) 2004-01-09 2005-01-07 Verwendung von pilocarpin für die behandlung von hypoptyalismus

Country Status (11)

Country Link
US (2) US20080241120A1 (de)
EP (1) EP1701721B1 (de)
AT (1) ATE451101T1 (de)
DE (1) DE602005018159D1 (de)
DK (1) DK1701721T3 (de)
ES (1) ES2336578T3 (de)
FR (1) FR2864901B1 (de)
PL (1) PL1701721T3 (de)
PT (1) PT1701721E (de)
SI (1) SI1701721T1 (de)
WO (1) WO2005067924A1 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070077300A1 (en) * 2005-09-30 2007-04-05 Wynn David W Oral compositions containing a salivation inducing agent
FR3010634A1 (fr) 2013-09-13 2015-03-20 Pf Medicament Compositions pharmaceutiques a base de tensioactif vegetal pour le traitement de l'hyposialie
FR3010635B1 (fr) 2013-09-13 2017-01-20 Pf Medicament Compositions pharmaceutiques a base d'agent filmogene pour le traitement de l'hyposialie
RU2554504C1 (ru) * 2014-02-20 2015-06-27 Андрей Константинович Иорданишвили Способ лечения лекарственной сиалоаденопатии

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB941664A (en) 1959-02-19 1963-11-13 Henry Thompson Stanton Jr Buccal or sublingual tablet containing carbohydra e enzyme for controlling inflammation
DK0502690T3 (da) * 1991-03-05 2000-05-22 Ajinomoto Kk Cyclopropanderivat
WO1994001108A1 (en) * 1992-07-02 1994-01-20 Theratech, Inc. Controlled release pilocarpine delivery system
US5731338A (en) * 1992-07-02 1998-03-24 Oramed, Inc. Controlled release pilocarpine delivery system
JPH07330602A (ja) 1994-06-13 1995-12-19 Nitto Denko Corp 経皮吸収型ピロカルピン製剤
FR2737661B1 (fr) * 1995-08-08 1997-10-31 Mgi Pharma Inc Composition pharmaceutique sous forme de comprimes comprenant du chlorhydrate de pilocarpine
AU783208B2 (en) * 1999-12-09 2005-10-06 Novartis Vaccines And Diagnostics, Inc. Method for administering a cytokine to the central nervous system and the lymphatic system
US20030185884A1 (en) * 2002-04-01 2003-10-02 Singh Nikhilesh Nihala Therapeutic agent delivery compositions for buccal cavity absorption of pilocarpine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2005067924A1 *

Also Published As

Publication number Publication date
FR2864901B1 (fr) 2007-10-05
FR2864901A1 (fr) 2005-07-15
WO2005067924A1 (fr) 2005-07-28
SI1701721T1 (sl) 2010-03-31
DE602005018159D1 (de) 2010-01-21
US20110301213A1 (en) 2011-12-08
ATE451101T1 (de) 2009-12-15
DK1701721T3 (da) 2010-04-12
US20080241120A1 (en) 2008-10-02
US9119775B2 (en) 2015-09-01
ES2336578T3 (es) 2010-04-14
EP1701721B1 (de) 2009-12-09
PL1701721T3 (pl) 2010-05-31
PT1701721E (pt) 2010-03-03

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